Recurrent Pregnancy LossACOG District II, April 30, 2016
John T. Queenan, Jr., MDProfessor
Reproductive EndocrinologyDepartment of Obstetrics and Gynecology
University of Rochester Medical CenterRochester, NY
Conflict of Interest
I dont have financial interest or other relationships with the industry relative to the topics being discussed.
I will not discuss any drugs by their brand names
Lecture Objectives
After this lecture, participants should be able to: Describe the numerous causes of recurrent
pregnancy loss
Understand how to diagnose the anatomic, autoimmune, endocrine, infectious, and genetic factors associated with RPL
Formulate a diagnostic plan to identify treatable causes
Miscarriage
The most common complication of pregnancy (15-25%)
Definition: the spontaneous loss of a pregnancy before a fetus has reached viability.
Embryonic Loss after Implantation
Cycles Studied 623
Pregnancy Detected 152
Clinically Detected 102
Lost after clinical detection 4 (14%)
623 cycles in 197 ovulating women aged 25-35
Wilcox AJ et al NEJM 1988
Lost after hormonal detection 66 (43%)
Cycles Studied
623
Pregnancy Detected
152
Clinically Detected
102
Lost after clinical detection
4 (14%)
US Dept Health and Human ServicesSurvey of Married Women in the United States
5% have experienced two fetal losses
1-3% have experienced three or more losses
U.S Vital and Health Statistics Series 23, No. 11
Definitions of RSAb
Three, consecutive: used for epidemiologic studies
Clinical definitions:Three, any order2 (1st) or 1 (2nd) trimesterThree, [SAb, any anomaly, or stillborn], any orderTwo or three or more ACOG 2011Two or more ASRM 2012
Continuum of Causation
LATE IUGR Retardation CNS disorders Delayed growth
and development Stillbirth
EARLY Biochemical
pregnancy Missed Abortion Spontaneous
losses
from Genetics, Obstetrics & Gynecology. Simpson, Elias 3rd ed.
Etiologies
Anatomic Autoimmune Endocrine Infectious Genetic Idiopathic (~40%)
Anatomic Causes10-15% of patients presenting with RSAb
Cervical Incompetence
Uterine septum Adhesions Polyps Fibroids Mllerian Anomalies
Uterine AnomaliesDiagnosis may be aided by MRI, 3-D sono, laparoscopy
Cerclage: for h/o 2nd trimester loss or progressive cervical shortening
Uterine Septum
80-90% of anomaliesin RSAb pts.
SAb rate for the septate uterus is 65%
After resection, 80% term delivery, 5% preterm delivery, 15% SAb rate
Grimbizis GF et al Hum Reprod Update 7:161, 2001
Definite Causes of IUA (shermans) in 1856 CasesTRAUMA AFTER PREGNANCY
Curettage after abortionPostpartum curettageCesarean SectionEvacuation of molar pregnancy
%67 222
0.6
Schenker, Margalioth. Fertil Steril 1992
Definite Causes of IUA (shermans) in 1856 Cases
PREGNANCY w/o TRAUMAPostpartum, post abortal
TRAUMA w/o PREGNANCYMyomectomyD + CEndo. Biopsy/polypectomy
INFECTION Pelvic TB
%1.5
1.31.20.5
4.0
Schenker, Margalioth. Fertil Steril 1992
shermans syndromeCase Series only. No RCTs
After hysteroscopic resection in 187 subjects: 76% conceived. Of those, 80% went to term, 18% aborted, 2% ectopic
Valle and Sciarra Am J Obstet Gynecol 1988
85% viable pregnancy rate after resection and short-term IUD placement
Ismajovich et al J Reprod Med 1985
Polyps and fibroids within the cavity should be excised if causing symptoms or are the only RSAb factor found
Polyps
Fibroid
Intramural fibroids that do not distort the cavity can grow up to 5-7 cm before they affect implantation
Endocrine Causes
Rules of Thumb: Well-controlled DM is not associated with
increased risk of RSAb
Significant thyroid disease and Diabetes are associated with increased risk, but are almost always clinically evident before RSAb.
Hypothyroidism screening
ACOG says no longer recommended
A high prevalence (3-10%) in reproductive age women supports checking TSH
Increased miscarriage rate for patients with hypothyroidism + subclinical hypothyroidism
Correction to the euthyroid state is simple, and you should aim for TSH < 2.5 U/ml
Speroff, Fritz. 8th ed
Hypothyroidism: confirmed
Levothyroxine requirements increase in 85% of pregnant patients
Onset as early as 5th week of gestation
Given the importance of the euthyroid state on fetal development, recommend increase levothyroxine dose 30% once pregnancy is confirmed
Alexander et al New England J Med 2004
Prolactin
64 patients with 2 or more losses and Prolactin
85.7% live born rate when treated with dopamine agoinst
52.4% live born rate if untreated
Hirahara F et al Fertil Steril 1998
The role of P4 in RSAbTwo Meta-analyses of patients
prospectively randomized to Placebo vs. Progesterone failed to show any benefit of Progesterone in preventing SAb in patients with prior sporadic miscarriage.
Goldstein P et al. Br J Obstet Gynaecol 1989; 96:265-74Oates-Whitehead TM Cochrane Database Syst Rev 2003
The role of P4 in RSAbHowever, a subgroup analyses of
women with recurrent miscarriage suggests that progesterone use in the first trimester might be of benefit.
Goldstein P et al. Br J Obstet Gynaecol 1989; 96:265-74Oates-Whitehead TM Cochrane Database Syst Rev 2003
AUTOIMMUNE RSAbAntiphospholipid Syndrome
Laboratory: Positive if present on two occasions at least 12 wks apart
Lupus Anticoagulant Kaolin Clotting Time
Russells Viper Venom Test
AntiCardiolipin Antibody IgM or IgG (>99 %ile)
Beta2-Glycoprotein 1 Antibodies IgM or IgG (>99 %ile)
ACOG Practice Bulletin #118, 2011
Cochrane Database of Systematic Reviews
RSAb with APS (+LAC or +ACL):
Treatment with unfractionated heparin and baby ASA reduces pregnancy losses by 54% (Level 1 evidence)
No advantage: LMWH vs. unfractionated No advantage: low dose vs. high dose
unfractionated heparin
AUTOIMMUNE RSAb
Many patients (and many MDs) are tempted to use anticoagulation/Baby ASA for presumed autoimmune RSAb.
Borderline LAC and/or ACL titers Elevated titers once, not confirmed >12 wks
later Frustration with no other etiology found
ALFIE StudyAnticoagulants for Living Fetuses
4 yr study, 8 academic centers 364 women with 2 or more losses Negative RPL work-up Randomized to: ASA, LMW Heparin/ASA, or
placebo
Trial halted early on the basis of futility.
Kaansdorp S et al N Engl J Med March 24, 2010
Inherited
Factor V LeidenPGMAnti-Thrombin IIIProtein SProtein C MTHFR
Are prevalent in the general population
Were previously thought to cause RSAb
Autoimmune RSAbThrombophilias
Prevalence of Thrombophilias
Factor V Leiden 3-8% Prothrombin G20210A mutation 1-4% *Protein C deficiency - 0.15-0.8% *Protein S deficiency 0.1% Antithrombin III deficiency 1/5000 *Hyperhomocysteinemia (MTHFR mutation)
11%Thrombophilias collectively present in up to 20% of Western population
* Results affected by pregnancy
AUTOIMMUNE RSAbInherited Thrombophilias
Causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes.
Inherited thrombophilia testing in women who have experienced recurrent fetal loss is not recommended because it is unclear whether anticoagulation reduces recurrence.
ACOG Practice Bulletin #113, 2010
Idiopathic RSAb (~40%)
After three consecutive losses, the chance for a liveborn in the next pregnancy is 70%
No therapy is often a valid approach TLC has proven benefits in some
studies
Cochrane Database of Systematic Reviews
Idiopathic RSAbNo effect from:
Vitamin supplementation (2005) Bedrest before 23 weeks (2005) Immunotherapy (2005) Anticoagulants (2005) Human chorionic gonadotropin (2005)
Cochrane Reviews 2005
Cochrane Database of Systematic Reviews
Idiopathic RSAbNo effect from:
Anticoagulants for women w/o APAb Any vitamins taken before 20 wks IVIG Paternal cell immunizations Third party donor leukocytes
Cochrane Reviews 2007
Internet as a portal (for misinformation)
Automimmunity has no symptoms What your doctor isnt telling you Miscarriages are occurring at implantation
Steroids Acupuncture Plaquenil Antibiotics Intralipid Herbal remedies IVIG
CHRONIC ILLNESS
Any systemic disease which may compromise the host, the uterine vasculature in particular, may be a cause of RSAb.
Examples include: heart disease, chronic hypertension, renal failure, collagen vascular disease, uncontrolled DM
Obesity (BMI>30 vs.19-25)
Odds Ratio C.I. P
First Trimester Loss 1.2 1.01-1.46 0.04
Recurrent Miscarriage 3.5 1.03-12.01 0.04
Lashen et al Hum Reprod 2004; 19:1644-46.
Environmental Exposures
Tobacco Alcohol Caffeine Lead Mercury PCBs Pesticides Radiation
Chromosomal Abnormalities in the aborted emb
